Brain volume change following anti-amyloid β immunotherapy for Alzheimer's disease: amyloid-removal-related pseudo-atrophy

Christopher R S Belder 1, Delphine Boche 2, James A R Nicoll 2, Zane Jaunmuktane 3, Henrik Zetterberg 4, Jonathan M Schott 5, Frederik Barkhof 6, Nick C Fox 7

Affiliations Expand

PMID: 39304242 DOI: 10.1016/S1474-4422(24)00335-1

Abstract

Progressive cerebral volume loss on MRI is a hallmark of Alzheimer's disease and has been widely used as an outcome measure in clinical trials, with the prediction that disease-modifying treatments would slow loss. However, in trials of anti-amyloid immunotherapy, the participants who received treatment had excess volume loss. Explanations for this observation range from reduction of amyloid β plaque burden and related inflammatory changes through to treatment-induced toxicity. The excess volume changes are characteristic of only those immunotherapies that achieve amyloid β lowering; are compatible with plaque removal; and evidence to date does not suggest an association with harmful effects. Based on the current evidence, we suggest that these changes can be described as amyloid-removal-related pseudo-atrophy. Better understanding of the causes and consequences of these changes is important to enable informed decisions about treatments. Patient-level analyses of data from the trials are urgently needed, along with longitudinal follow-up and neuroimaging data, to determine the long-term trajectory of these volume changes and their clinical correlates. Post-mortem examination of cerebral tissue from treated patients and evaluation of potential correlation with antemortem neuroimaging findings are key priorities.

 

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Conflict of interest statement

Declaration of interests DB has been a consultant or advisor relating to Alzheimer immunisation programmes for: Elan Pharmaceuticals (travel and accommodation) and Biogen (consultancy fees). JARN has been a consultant or advisor relating to Alzheimer immunisation programmes for: Elan Pharmaceuticals (travel and accommodation), GlaxoSmithKline (consultancy fees), Novartis, Roche (consultancy fees), Janssen (consultancy fees), Pfizer, Biogen (consultancy fees, travel, and accommodation), and Eisai. HZ has served at scientific advisory boards or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche; is chair of the Alzheimer's Association Global Biomarker Standardization Consortium; is a cofounder of Brain Biomarker Solutions in Gothenburg (Brain Biomarker Solutions), which is a part of the GU Ventures Incubator Program. JMS has received tracer from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) and Alliance Medical and has consulted for Roche Pharmaceuticals, Biogen, and Eli Lilly. FB has received consulting fees from Combinostics, Roche, and IXICO; has participated in data safety monitoring or advisory boards for EISAI, Biogen, Prothena, and Merck; and is a cofounder of Queen Square Analytics. NCF reports consulting fees from Biogen, Eisai, Ionis, Lilly, Roche/Genentech, and Siemens—paid to University College London; he has served on a data safety monitoring board for Biogen. All other authors declare no competing interests.